Fig. 2. The UPR activates autophagy.

ERS mainly mediates autophagy through four pathways: PERK, IRE1α, ATF6, and Ca²⁺, of which the key regulator is C/EBP homologous protein (CHOP). When ERS is activated, IRE1α acts on Beclin1 through the tumor necrosis factor receptor-associated factor 2 (TRAF2) and Jun N-terminal kinase (JNK) pathway to promote autophagy; ATF6 activates its downstream death-associated protein kinase 1 to activate autophagy through Beclin1; all three UPR pathways can regulate autophagy by activating CHOP protein. In addition, Ca²⁺ can also participate in autophagy through protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII).